Anti-convulsant compounds



United States Patent 3,271,404 ANTI-CONVULSANT COMPOUNDS Rudolf G. Griot, Florham Park, N.J., assignor to Sandoz, Inc., Hanover, N.J., a corporation of New York No Drawing. Filed July 25, 1963, Ser. No. 297,708 7 Claims. (Cl. 260-2941) in which R is hydrogen, lower alkyl such as methyl, aralk-yl such as benzyl, mononuclear carboxylic such as phenyl or cycloalkyl such as cyclohexyl, R is lower alkyl such as methyl, aralkyl such as benzyl, mononuclear carboxylic such as phenyl or cycloalkyl such as cyclohexyl, and n is an integer of from 2 to 5.

The compounds of the present invention can be produced either from the intermediates or the final products of said copending application in accordance with the fol lowing reaction scheme:

[Uneyclized intermediates of copending application (CHZ)n Pd/Alox 2 i Glacial 011 0 0 011 R1 0 H on Pd/Alox 1 mole i Glacial 011 0 0 011 R1 O\H/O H2 R [Cyclols of (CH2). copending 0 N\ application] R R and n have the meanings set forth above. The uncyclized intermediates and the cyclols used to produce the compounds of the present invention are prepared as described in the said copending application.

The compounds of this invention are produced by the reductive cleavage of the benzyl group of the above uncyclized intermediates in the presence of concentrated or glacial acetic acid while adding two moles of hydrogen and employing palladium on alumina as catalyst or by hydrogenating the above cyclols while adding one mole of hydrogen in the presence of concentrated or glacial acetic acid and employing palladium on alumina as catalyst.

The invention is illustrated by the following nonlimitative examples.

3,271,404 Patented Sept. 6, 1966 ice EXAMPLE 1 8-methyl-7-0xa-1-azabicycl0- [4.3.0] -n0nan0ne-(9) The above compound was obtained in 70% yield from 6-hydroxy 8 methyl 7 oXa 1 azabicyclo-[4.3.0.]- nonanone-(9) by hydrogenation with one mole of hydrogen in glacial acetic acid on palladium/alumina as catalyst or from N-(Z-benzyloxypropionyl)-piperidone by hydrogenation under the same conditions with two moles of hydrogen. [B. Pt. 79 C./0.08 mm.;

infrared: 1700 cm.- (lactam C=O)].

C H NO C, 61.9%; H, 8.4%; N, 9.2%; O, 20.9%

(calculated). C, 61.4%; H, 8.4%; N, 9.0%; O, 20.6% (found).

EXAMPLE 2 8,8-dimethyl-7-oxa-1 -azabicycl0- [4.3 .0.]-n0nan0ne'-(9) This compound was obtained by the hydrogenation of N-(a-benzyloxybutyryl)-piperidone in glacial acetic acid with two moles of hydrogen and a palladium catalyst. [B. Pt. 105-110 C./12 mm.; n =1.4762; infrared: 1705 cm. (lactam --CO); NMR: multiplet at 289 c.p.s. (H in position 7), two singlets at 278 c.p.s. and 274 c.p.s. respectively, due to the two CH groups].

CQH15NO2I Calculate'dC, H, 8.9%; N, 8.3%. Found: C, 63.4%; H, 9.4%; N, 8.4%.

EXAMPLE 3 9-methyl-8-0xa-1-azabicycl0-[5.3.0.1-decan0ne-(10) EXAMPLE 4 9,9-dz'melhyl-8-0xa-I -azabicycl0- [5 .3.0.]-decan0ne-(1 0) H CH 0 i/ This compound was obtained by the hydrogenation of N-(a-benzyloxyisobutyryl)-caprolactam in glacial acetic acid with two moles of hydrogen and a palladium catalyst.

[B. Pt. 105 C./13 mm., n =1.4793; infrared: 1700 cm. (lactam -CO); NMR: triplet of the H in position 7 at 310 c.p.s. (J=3 c.p.s.); two singlets of the two CH groups at 74 c.p.s. and 78 c.p.s. respectively].

C10H17NO2I Oalcu1ated-H, 9.4%; N, 7.6%. Found: H, 9.4%; N, 7.5%.

N -(a-b nzyl0xyis0butyryl -capr0lactam The above N-(m-benzyloxyisobutyryl)-capr0lactam of the formula:

aTo CHzCeHs O EXAMPLE 5 9-phenyl-8-0xa-1-azabicycl0-[5.3.0.] -decan0ne-(10) This substance was obtained by the hydrogenation of N-(a-benzyloXy-phenylacetyl)-caprolactam prepared as set forth in the aforesaid copending application with 2 moles of hydrogen in acetic acid solution and a palladium/ alumina catalyst.

Yield: 59%. [B.p. 140 C./0.01 mm.; n =1.5458].

C I-1 N0 1 OaleulatedC, 72.7%; H, 7.4%; N, 6.1%. Found: C, 72.7%; H, 7.6% N, 6.3%.

In similar manner, 9 benzyl 8 oxa-l-azabicyclo- [5.3.0.]-decanone-(10) was prepared by hydrogenation of the corresponding N-(a-benzyloXy-benzylacetyl)- caprolactam.

What is claimed is:

1. A compound of the formula:

in which R is selected from the group consisting of hydrogen, lower alkyl, benzyl, phenyl and cyclohexyl, R is selected from the group consisting of lower alkyl, benzyl, phenyl and cyclo hexyl and n is an integer in the range of 2 to 3.

2. 8-methyl-7-oxa-l-azabicyclo [4.3 .0.]-nonanone-(9') 3. 8,8 dimethyl-7-oxa-l-azabicyclo[4.3.0.1-nonanone- (9).

4. 9rnethyl-8-oxa-l-azabicyclo [5 3.0.] -decanone-(10) 5. 9,9 dimethyl-8-oxa-l-azabicyclo[5.3.0.]-decanone- (10).

6. 9-phenyl-8-oxa-l-azabicyclo [5.3.0.] -decanone-( 10) 7. 9-benZyl-8-oxa-l-azabicyclo[5.3.0.]-decanone-(10).

References Cited by the Examiner Stich et al.: Helv. Chim. Acta, vol. 46, pp. 1151-1157 (1963), (published June 17, 1963).

ALEX MAZEL, Primary Examiner.

NICHOLAS S. RIZZO, Examiner.

ALTON D. ROLLINS, RICHARD J.GALLAGHER,

Assistant Examiners. 

1. A COMPOUND OF THE FORMULA 